The overall goal of this grant is to understand how apolipoproteins control lipoprotein metabolism and by this mechanism influence atherosclerosis susceptibility. The apolipoprotein genes have now been isolated, sequenced, and mapped. Consequently, it is now possible to create genetically altered animals in which apolipoprotein genes are over or under expressed to test directly specific hypotheses about how apolipoproteins control lipoprotein metabolism. Specifically, we will study how the apo A-I and apo CIII genes regulate lipoprotein metabolism, particularly the levels of HDL and triglyceride-rich lipoproteins, and influence atherosclerosis susceptibility. We expect that the insights gained from these studies will be useful in understanding human lipoprotein disorders. The specific aims are: 1. Characterize the role of the apo A-1 gene in determining HDL metabolism and atherosclerosis susceptibility. 1a. To increase atherosclerosis susceptibility in the mouse by knocking out the endogenous apo A-I gene. 1b. To study the influence of HDL levels on atherosclerosis progression and regression. 1c. To test whether HDL levels influence tissue cholesterol metabolism. 1d. To define how apo A-1 influences particle size distribution, HDL CE and apo A-I FCR, and HDL-CETP interaction. 1e. To determine the cis and trans acting factors controlling intestinal expression of apo A-1. 2. Characterize the role of the apo CIII gene in regulating triglyceride-rich lipoprotein metabolism. 2a. To study the mechanism of hypertriglyceridemia and determine its effect on atherosclerosis susceptibility in human apo CIII transgenic mice. 2b. To examine the mechanism underlying the association of high triglycerides and low HDL cholesterol levels in human apo CIII transgenic mice. 2c. To determine whether mutations at the apo CIII gene locus play a role in human hypertriglyceridemia. 2d. To create an apo CIII deficient mouse and use it to determine how apo CIII influences lipoprotein metabolism.